Trans-6-(2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)-ethyl)-or ethenyl)tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis

ABSTRACT

Certain trans-6-[2-(N-heteroaryl-3,5-disubstituted) pyrazol-4-yl)ethyl]- or ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones and the corresponding ring-opened acids, esters and N-oxides derived therefrom which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful hypolipidemic or hypocholesterolemic agents. Pharmaceutical compositions containing such compounds, and a method of inhibiting the biosynthesis of cholesterol employing such pharmaceutical compositions are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.048,473 filed May 18, 1987, now U.S. Pat. No. 4,808,621, issued Feb. 28,1989, which is a continuation-in-part of application Ser. No. 882,327filed July 7, 1986, abandoned.

BACKGROUND OF THE INVENTION

The present invention is related to compounds and pharmaceuticalcompositions useful as hypocholesterolemic and hypolipidemic agents.More particularly, this invention concerns certaintrans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)ethyl]- orethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones and the correspondingring-opened acids derived therefrom which are potent inhibitors of theenzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoAreductase), pharmaceutical compositions containing such compounds, and amethod of inhibiting the biosynthesis of cholesterol employing suchpharmaceutical compositions.

High levels of blood cholesterol and blood lipids are conditionsinvolved in the onset of arteriosclerosis. It is well known thatinhibitors of HMG-CoA reductase are effective in lowering the level ofblood plasma cholesterol, especially low density lipoprotein cholesterol(LDL-C), in man (cf. M. S. Brown and J. L. Goldstein, New EnglandJournal of Medicine, 305, No. 9, 515-517 (1981). It has now beenestablished that lowering LDL-C levels affords protection from coronaryheart disease (cf. Journal of the American Medical Association, 251, No.3, 351-374 (1984).

Moreover, it is known that certain derivatives of mevalonic acid(3,5-dihydroxy-3-methylpentanoic acid) and the corresponding ring-closedlactone form, mevalonolactone, inhibit the biosynthesis of cholesterol(cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102: 270 (1959)and F. H. Hulcher, Arch. Biochem. Biophys., 146: 422 (1971)).

U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 disclose thefermentative production of a natural product, now called compactin,having an inhibitory effect on cholesterol biosynthesis. Compactin hasbeen shown to have a complex structure which includes a mevalonolactonemoiety (Brown et al., J. Chem. Soc. Perkin I (1976) 1165.

U.S. Pat. No. 4,255,444 to Oka et al. discloses several syntheticderivatives of mevalonolactone having antilipidemic activity.

U.S. Pat. Nos. 4,198,425 and 4,262,013 to Mitsue et al. disclose aralkylderivatives of mevalonolactone which are useful in the treatment ofhyperlipidemia.

U.S. Pat. No. 4,375,475 to Willard et al. discloses certain substituted4-hydroxytetrahydropyran-2-ones which, in the 4(R)-trans-stereoisomericform, are inhibitors of cholesterol biosynthesis.

U.S. Pat. No. 4,613,610 discloses certain pyrazole analogs andderivatives of mevalonolactone having utility as hypolipoproteinemic andantiatherosclerotic agents.

SUMMARY OF THE INVENTION

In accordance with the present invention, there are provided certaintrans-6-[2-N-heteroaryl-3,5-substituted- pyrazol-1-yl)ethyl]- orethenyl]tetrahydro-4-hydroxy-2H- pyran-2-ones and the correspondingring-opened hydroxy-acids derived therefrom which are potent inhibitorsof cholesterol biosynthesis by virtue of their ability to inhibit theenzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAreductase).

In particular, in its broadest aspect the present invention providescompounds of structural Formula I ##STR1## wherein R₁ is 2-, 4-, or5-pyrimidinyl; 2-pyrazinyl; 2-, 3-, or 4-pyridinyl; 2-, 3-, or4-quinolinyl; 3-phthalazinyl; 9-acridinyl, 3-, 4-, or 5-pyrazolyl; 2-,4-, or 5-imidazolyl; 2-benzimidazolyl, 2-benzothiazolyl; 2-, or3-indolyl, 2-, or 3-furanyl; or 2-, or 3-thienyl, or 2-, or 3-pyrrolyl.

R₂ is alkyl of from one to three carbon atoms, trifluoromethyl,dialkylamino in which alkyl is one to four carbon atoms, pyrrolidino,piperidino, morpholino or piperazino.

R₅ is a saturated carbocyclic ring of from four to seven carbon atomsoptionally substituted with alkyl of from one to three carbon atoms;2-norbornyl; 2-norbornenyl; bicyclo[2.2.2]octyl; or ##STR2## where R₃and R₄ are independently hydrogen, alkyl of from one to three carbonatoms, chlorine, or fluorine.

The dotted line in the bridging group connecting the substitutedpyrazole group to the pyran-2-one ring is meant to indicate that thebridging group may be either an ethyl (i.e. --CH₂ CH₂ --) or ethenyl(i.e. --CH═CH--) group.

The dotted lines in the pyrazole nucleus in Formula I above are meant toindicate that the substituent R₁ may be attached to the nitrogen atom atposition 1, with double bonds between the atoms at positions 2-3 and 4-5or, alternatively, R₁ may be attached to the nitrogen atom at position 2with double bonds between the atoms at positions 1-5 and 3-4. (Allposition numbers corresponding to those in structural Formula I above.)

Also contemplated as falling within the scope of the present inventionare the hydroxy acids or esters, pharmaceutically acceptable saltsthereof, corresponding to the opening of the lactone ring of thecompounds of structural Formula I above, N-oxides, sulphoxides orsulphones thereof.

In another aspect, the present invention provides pharmaceuticalcompositions useful as hypolipidemic or hypocholesterolemic agentscomprising a hypolipidemic or hypocholesterolemic effective amount of acompound in accordance with this invention as set forth above, incombination with a pharmaceutically acceptable carrier.

In yet another aspect, the present invention provides a method ofinhibiting cholesterol biosynthesis in a patient in need of suchtreatment by administering an effective amount of a pharmaceuticalcomposition as defined above.

DETAILED DESCRIPTION

The compounds of the present invention comprise a class oftrans-6-[2-N-heteroaryl-3,5-substituted-pyrazol-1-yl)ethyl]- orethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones and the correspondingring-opened hydroxy-acids derived therefrom in which the substitutedpyrazole nucleus is attached, through an ethylene or ethenylene group tothe remainder of the molecule. When the bridging group between thesubstituted pyrazole ring and the remainder of the molecule is ethyl,the configuration in the lactone ring is R*R*. Preferred compounds ofthe present invention are those in which the bridging group between thesubstituted pyrazole ring and the remainder of the molecule is ethenyl,i.e. --CH═CH--, most preferably in the (E)-trans form and theconfiguration in the lactone ring is R*S*.

In the compounds of the present invention, position 3 of the pyrazolenucleus (as numbered in structural Formula I above) is substituted withalkyl of from one to three carbon atoms, trifluoromethyl, dialkylaminoin which alkyl is one to four carbon atoms, pyrrolidino, piperidino,morpholino or piperazino. Preferred substituents at this position arelower alkyl or dimethylamino, with 1-methylethyl being most preferred.

Position 5 of the pyrazole nucleus (as numbered in structural Formula Iabove) is substituted with phenyl which is monosubstituted with alkyl offrom one to three carbon atoms, fluorine, chlorine or trifluoromethyl,or phenyl which is disubstituted with two groups independently selectedfrom alkyl of from one to three carbon atoms, fluorine, chlorine, ortrifluoromethyl. Preferred compounds of the present invention are thosein which position 5 is substituted with 4-fluorophenyl.

The compounds of structural Formula I above possess two asymmetriccarbon centers, one at the 4-hydroxy position of the pyran-2-one ring,and the other at the 6-position of the pyran-2-one ring where thealkylpyrazole group is attached. This asymmetry gives rise to fourpossible isomers, two of which are the R-cis- and S-cis- isomers and theother two of which are the R-trans- and S-trans- isomers. This inventioncontemplates only the trans- form of the compounds of Formula I above.

Examples of compounds contemplated as falling within the scope of thepresent invention include, but are not limited to the following:

[4α,6α]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6α]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-quinolinyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-quinolinyl)-1-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-1,3'-bi-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-1,3'-bi-1-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β])-6-[2-[5-(4-Fluorophenyl)-1-(1H-imidazol-4-yl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-1-(1H-imidazol-4-yl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[1-(1H-Benzimidazol-2-yl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[1-(1H-Benzimidazol-2-yl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[1-(9-Acridinyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[1-(9-Acridinyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-thienyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-thienyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[5-(4-Fluorophenyl)-1-(2-furanyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-1-(2-furanyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(1H-pyrrol-2-yl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(1H-pyrrol-2-yl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

-[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β(E)]-6-[2-[5-[4-Fluorophenyl-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

One reaction sequence which is used to prepare compounds of the presentinvention is depicted schematically in the following Reaction Sequence(1).

The known or commercially available heteroaryl hydrazine, IV, is reactedwith with the desired 1,3-disubstituted diketone, V, to produce thecyclized N-heteroaryl-substituted pyrazole, VIa or VIb. This additionmay occur in either of two ways, leading to a substituted pyrazoleaddition product in which the heterocyclic ring substituent resides oneither of the two nitrogen atoms of the pyrazole ring. The predominantproduct of this reaction, however, is the regioisomer in which theheterocyclic ring is attached to the nitrogen atom adjacent to thecarbon which bears the substituted phenyl group (i.e., VIa).

REACTION SEQUENCE (1) ##STR3##

The substituted pyrazole VI is next halogenated by the action ofN-bromo- or N-iodosuccinimide in a polar solvent such asdimethylformamide, typically at a temperature below about 10° C. toproduce the halogenated derivatives, VII, where X is iodine or bromine.

The 4-halopyrazole compounds, VII, are coupled with6-ethenyl-2,2-dimethyl-1,3-dioxane-4-acetic acid, methyl or ethyl ester,employing the Heck Reaction (cf. R. F. Heck, Organic Reactions, 27:345-390 (1982) to form VIII.

The pyrazolyl(ethenyl)-1,3-dioxanes, VIII, are saponified and theprotecting group removed in the usual manner to produce thecorresponding dihydroxyacids, IX, which are employed per se, or as apharmaceutically acceptable salt, in the pharmaceutical method of thisinvention. Alternatively, the acids, IX. may be cyclized to thecorresponding lactones, X, under mild conditions by a dehydrating agentsuch as dicyclohexylcarbodiimide.

In a further alternative, the unsaturated dioxanes, VIII, arecatalytically reduced under hydrogen to produce the correspondingsaturated compounds, XI, which are saponified and deprotected in theusual manner to produce the saturated dihydroxyacids, XII. As with theunsaturated dihydroxyacids, the saturated dihydroxyacids, XII, areemployed per se, or as a pharmaceutically acceptable salt in thepharmaceutical method of this invention, or are cyclized to thecorresponding saturated lactones, XIII, generally by heating underreflux in toluene with concomitant azeotropic removal of water.

An alternate reaction sequence used to prepare compounds of the presentinvention beginning with compound VII of Reaction Sequence (1) isdepicted schematically in the following Reaction Sequence (2).

REACTION SEQUENCE (2) ##STR4##

For example, the 4-halopyrazole compounds (VII) are coupled with ethylacrylate, employing the Heck reaction (cf. R. F. Heck, Org. Reac., 27,345-390 (1982)). The esters (a) are reduced at -78° C. by the action ofdiisobutyl aluminum hydride to yield the alcohols (b) which are thenoxidized to the corresponding aldehydes (c) with manganese dioxide.Aldol condensation of the aldehydes (c) with the sodium lithium dianionof ethyl acetoacetate at -78° C. in tetrahydrofuran (cf. Kraus et al.,J. Org. Chem., 48, 2111 (1983)) gives the 5-hydroxy-β-keto esters (d).The products of this condensation are then reduced in a sequence ofsteps in which they are first dissolved in a polar solvent such astetrahydrofuran under dry air atmosphere. A small excess of triethylborane and catalytic amounts of pivalic acid (2,2-dimethylpropanoicacid) are next added. The mixtures are stirred at room temperature for ashort period, then cooled to -78° C.; dry methanol is added followed bysodium borohydride. The mixtures are kept at -78 ° C. for six hoursbefore treating with ice cold hydrogen peroxide. The substituted3,5-dihydroxy-6-heptenoic acid ethyl esters (IX) are isolated having thepreferred R* S* configuration. The esters (IX) may be hydrolyzed to thesodium salts. The esters (IX) or the free acids produced byacidification of the sodium salts can be dehydrated to the lactones (X)by heating the acid in an inert solvent such as toluene with concomitantazeotropic removal of water.

The ring-opened hydroxy acids or esters of structural formulae IX andXII above are intermediates in the synthesis of the lactone compounds ofFormula I and may be used in their free acid form or in the form of apharmaceutically acceptable metal or amine salt in the pharmaceuticalmethod of the present invention. These acids react to formpharmaceutically acceptable metal and amine salts. The term"pharmaceutically acceptable metal salt" contemplates salts formed withthe sodium, potassium, calcium, magnesium, aluminum, iron, and zincions. The term "pharmaceutically acceptable amine salt" contemplatessalts with ammonia and organic nitrogenous bases strong enough to formsalts with carboxylic acids. Bases useful for the formation ofpharmaceutically acceptable nontoxic base addition salts of compounds ofthe present invention form a class whose limits are readily understoodby those skilled in the art.

The free acid form of compounds of the present invention may beregenerated from the salt form, if desired, by contacting the salt witha dilute aqueous solution of an acid such as hydrochloric acid.

The base addition salts may differ from the free acid forms of thecompounds of this invention in such physical characteristics assolubility and melting point, but are otherwise considered equivalent tothe free acid form for the purposes of this invention.

The compounds of the present invention may exist in solvated orunsolvated form. In general, the solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol and the like, are equivalentto the unsolvated forms for the purposes of this invention.

The compounds of the present invention in lactone or free acid form maybe further converted to their corresponding N-oxides by mild oxidationmethods known in the art using, for example, peracetic acid, perbenzoicacids or hydrogen peroxide with an appropriate solvent and an optionalcatalyst.

The compounds of this invention are useful as hypocholesterolemic orhypolipidemic agents by virtue of their ability to inhibit thebiosynthesis of cholesterol through inhibition of the enzyme3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).

The ability of compounds of the present invention to inhibit thebiosynthesis of cholesterol was measured by two methods. A first method(designated CSI screen) utilized the procedure described by R. E. Duganet al., Archiv. Biochem. Biophys., (1972), 152, 21-27. In this method,the level of HMG-CoA enzyme activity in standard laboratory rats isincreased by feeding the rats a chow diet containing 5% cholestyraminefor four days, after which the rats are sacrificed.

The rat livers are homogenized, and the incorporation of ¹⁴ C-acetateinto nonsaponifiable lipid by the rat liver homogenate is measured. Themicromolar concentration of compound required for 50% inhibition ofsterol synthesis over a one-hour period is measured, and expressed as anIC₅₀ value.

A second method (designated COR screen) employed the procedure detailedby T. Kita, et al., J. Clin. Invest., (1980), 66: 1094-1100. In thismethod, the amount of ¹⁴ C-HMG-CoA converted to ¹⁴ C-mevalonate in thepresence of a purified enzyme preparation of HMG-CoA reductase wasmeasured. The micromolar concentration of compound required for 50%inhibition of cholesterol synthesis was measured and recorded as an IC₅₀value.

The activity of representative examples of compounds in accordance withthe present invention appears in Table 1, and are compared with that ofthe prior art compound, compactin.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersable granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecompounds is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppositories, a low-melting wax such as a mixture offatty acid glycerides and cocoa butter is first melted, and the activeingredient is dispersed therein by, for example, stirring. The moltenhomogeneous mixture is then poured into convenient sized molds andallowed to cool and solidify.

                                      TABLE 1                                     __________________________________________________________________________     ##STR5##                                                                                                       IC.sub.50                                                                     (Micromoles/liter)                          Compound                                                                            X       R.sub.1 R.sub.2                                                                              R.sub.3                                                                         R.sub.4                                                                          CSI  COR                                    __________________________________________________________________________    1     CH.sub.2 CH.sub.2                                                                     1-(2-   CH(CH.sub.3).sub.2                                                                   H 4-F                                                                              0.039                                                                              0.11                                                 pryidinyl)                                                      2     CHCH    1-(2-   CH(CH.sub.3).sub.2                                                                   H 4-F                                                                              0.022                                                                              0.025                                                pyridinyl)                                                      3     CHCH    1-(2-   CH(CH.sub.3).sub.2                                                                   H 4-F                                                                              0.02 0.069                                                pyrazinyl)                                                      3     CHCH    1-(2-   CH(CH.sub.3).sub.2                                                                   H 4-F                                                                              0.024                                                                              0.018                                                pyrimidinyl)                                                    4     CHCH    1-(2-   CH(CH.sub.3).sub.2                                                                   H 4-F                                                                              0.032                                                                              0.059                                                benzothiazolyl)                                                 Compactin (Prior art)             0.026                                                                              0.028                                  __________________________________________________________________________

Powders and tablets preferably contain between about 5 to about 70% byweight of the active ingredient. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin,starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, alow-melting wax, cocoa butter, and the like.

The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier, which is thus in association with it. In asimilar manner, cachets are also included. Tablets, powders, cachets,and capsules can be used as solid dosage forms suitable for oraladministration.

Liquid form preparations include solutions suitable for oral orparenteral administration, or suspensions and emulsions suitable fororal administration. Sterile water solutions of the active component orsterile solutions of the active component in solvents comprising water,ethanol, or propylene glycol may be mentioned as examples of liquidpreparations suitable for parenteral administration.

Sterile solutions may be prepared by dissolving the active component inthe desired solvent system, and then passing the resulting solutionthrough a membrane filter to sterilize it or, alternatively, bydissolving the sterile compound in a previously sterilized solvent understerile conditions.

Aqueous solutions for oral administration can be prepared by dissolvingthe active compound in water and adding suitable flavorants, coloringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural or synthetic gums, resins, methyl cellulose, sodiumcarboxymethyl cellulose, and other suspending agents known to thepharmaceutical formulation art.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

In therapeutic use as hypolipidemic or hypocholesterolemic agents, thecompounds utilized in the pharmaceutical method of this invention areadministered to the patient at dosage levels of from 40 mg to 600 mg perday. For a normal human adult of approximately 70 kg or body weight,this translates to a dosage of from about 0.5 mg/kg to about 8.0 mg/kgof body weight per day.

The dosages, however, may be varied depending upon the requirements ofthe patient, the severity of the condition being treated, and thecompound being employed. Determination of optimum dosages for aparticular situation is within the skill of the art.

The following examples illustrate particular methods for preparingcompounds in accordance with this invention. These examples areillustrative and are not to be read as limiting the scope of theinvention as it is defined by the appended claims.

EXAMPLE 1 Preparation of[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-oneStep A--Preparation of 1-(4-fluorophenyl)-4-methyl-1,3-pentanedione

A mixture of 4-fluoroacetophenone (150 g, 1.09 mol) and ethylisobutyrate (126 g, 1.09 mol) in 1.5 liters of dioxane was addeddropwise under a nitrogen atmosphere to a vigorously stirred suspensionof hexane-washed sodium hydride (133 g, 3.25 mol, 58.8% NaH) in 3.0liters of dioxane. Vigorous evolution of gas ensued, after which themixture was heated to 80°-90° C. for four hours.

The mixture was then allowed to cool to room temperature after which itwas poured into six liters of 2 M hydrochloric acid. The resultingmixture was cooled to 0° C. with vigorous stirring and extracted fourtimes with 1-liter portions of chloroform.

The combined chloroform extracts were washed twice with 500 ml portionsof water, twice with 500 ml portions of brine solution, and then driedover anhydrous magnesium sulfate. The mixture was filtered to removeundissolved solids, and the filtrate was concentrated under vacuum.

Distillation of the residue yielded 116 g (50%) of1-(4-fluorophenyl)-4-methyl-1,3-pentanedione, b.p. 100°-110° C. at 1torr. The infrared spectrum of a thin film of the product showedprincipal absorption peaks at 2973 and 1603 reciprocal centimeters.

The 100 MHz proton magnetic resonance spectrum of the product indeuterochloroform showed peaks at 1.25 (d, J=7 Hz, 6H), 2.60 (m, J=7 Hz,1), 6.1 (m, 2H), 6.1 (s, 1H), 7.15 (m, 2H), and 7.9 (m, 2H) parts permillion downfield from the tetramethylsilane signal.

Step B--Preparation of2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyridine

To a solution of 10 g (48 mmol) of1-(4-fluorophenyl)-4-methyl-1,3-pentanedione in 100 ml of glacial aceticacid was added, under a nitrogen atmosphere at room temperature, 5.77 g(53 mmol) of 2-hydrazinopyridine.

This mixture was then heated at 60° C. for three hours, cooled to roomtemperature, and poured into 100 ml of water. The resulting mixture wasextracted with diethyl ether and the organic layer was separated, washedsuccessively with saturated sodium bicarbonate solution, water, andbrine. The ether solution was dried over anhydrous magnesium sulfate,and concentrated under vacuum.

The crude product was flash chromatographed on a silica gel column,eluting with 20% ethyl acetate in hexane to yield 8.7 g of2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyridine, mp80°-81° C.

The 200 MHz proton magnetic resonance spectrum of a deuterochloroformsolution of the product exhibited peaks at 8.35 (d, 1H); 7.0-7.8 (m,7H); 6.35 (s, 1H); 3.15 (m, 1H); and 1.3 (d, 6H) parts per milliondownfield from the tetramethylsilane signal.

Step C--Preparation of2-[4-bromo-5-(4-Fluorophenyl)-3-(1methylethyl)-1H-pyrazol-1-yl]pyridine

N-Bromosuccinimide (7.9 g, 28 mmol) was added to a mixture of2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1-pyrazol-1-yl]pyridine (7.89 g,28 mmol) and 30 ml of dimethylformamide at 0° C.

The resulting mixture was stirred at 0° C. for four hours and thenpoured into 100 ml of water. The white solid which precipitated wascollected by filtration and dried to yield 9.0 g of2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyridine,mp 98°-100° C.

The 200 MHz proton magnetic resonance spectrum of a deuterochloroformsolution of the product exhibited peaks at 8.3 (d, 1H); 7.0-7.8 (m, 7H);3.1-3.2 (m, 1H); and 1.4 (d, 6H) parts per million down field from thetetramethylsilane signal.

Step D--Preparation of cis-(±)-ethyl6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate

bis-(Tri-O-tolylphosphine) palladium (II) chloride (0.21 g, 2 mmol %)was added to a stirred solution of6-ethenyl-2,2-dimethyl-1,3-dioxane-4-acetic acid, ethyl ester (5.54 g,24.3 mmol) in 30 ml of a 50:50 mixture of triethylamine anddimethylformamide.

The mixture was heated to reflux (-120° C.) and 5 g (13.9 mmol) of2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyridinewas added. This mixture was heated under reflux for two hours, at whichpoint a further 0.15 g (1.5 mmol %) of catalyst was added. The mixturewas heated under reflux for another twenty-four hours during which anadditional 2 mmol % of catalyst was added to the mixture.

The mixture was then cooled to room temperature and poured into 50 ml ofwater. The mixture which resulted was extracted with diethyl ether, andthe ether extract washed successively with portions of water and brineand then dried over anhydrous magnesium sulfate.

The ether solution was concentrated, and the crude product was flashchromatographed on a silica gel column eluting with 20% ethyl acetate inhexane to yield 1.44 g of cis-(±)-ethyl6-[2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate.

The 200 MHz proton magnetic resonance spectrum of a deuterochloroformsolution of the product exhibited peaks at 8.2 (d, 1H); 6.9-7.7 (m, 7H);6.3 (d, 1H); 5.6 (dd, 1H); 4.3 (m, 2H); 4.0 (q, 2H); 3.2 (s, 1H); 2.56(dd, 1H); 2.4 (dd, 1H); and 1.3-1.6 (m, 17H) parts per million downfieldfrom the tetramethylsilane signal.

Step E--Preparation of (R*,R*)-7-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptenoicacid

A solution of 1.44 g (2.84 mmol) ofcis-(±)-ethyl-6-[2[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate in 15 ml ofethyl acetate was catalytically reduced under one atmosphere of hydrogengas in the presence of 20% Pd/C. at 25° C. for four days.

The catalyst was removed by filtration and the filtrate wasconcentrated. The residue was dissolved in 4 ml of 50:50tetrahydrofuran:1 molar hydrochloric acid and stirred for three hours.The mixture was then made basic by the addition of 25% aqueous sodiumhydroxide solution, and the mixture was stirred for thirty minutes.

This mixture was diluted with water, extracted with diethyl ether, andthen acidified. The acidified water layer was extracted twice with ethylacetate and the combined extracts were washed with brine and dried overanhydrous magnesium sulfate. Evaporation of the solvent yielded (R*,R*)-7-[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptanoicacid.

Step F--Preparation of[4α,6β]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

The crude (R*,R*)-7-[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptanoicacid from the previous step was lactonized by heating it under reflux intoluene for one hour with azeotropic removal of water. After cooling toroom temperature the mixture was concentrated and the residue was flashchromatographed on a silica gel column, eluting with 75% ethyl acetatein hexane to yield pure[4α,6β]-6-[2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,mp 182°-184° C. (after recrystallization from 10% ethyl acetate inhexane).

Analyzed for C₂₄ H₂₆ FN₃ O₂ : Calculated: C, 68.07%; H, 6.19%; N, 9.92%;Found: C, 67.76%; H, 6.18%; N, 9.57%.

The infrared spectrum of a potassium bromide pellet of the productexhibited principal absorption peaks at 2965, 2871, 1719, 1591, 1511,1478, 1228, 1145, and 1051 reciprocal centimeters.

The 200 MHz proton magnetic resonance spectrum of a deuterochloroformsolution of the product exhibited peaks at 8.82 (d, 1H); 7.0-7.9 (m,7H); 5.2 (d, 1H); 4.5 (m, 1H); 4.1 (m, 1H); 3.1 (h, 1H); 2.3-2.7 (m,4H); 1.6-1.8 (m, 4H); and 1.3 (d, 6H); parts per million downfield fromthe tetramethylsilane signal.

EXAMPLE 2 Preparation of[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-oneStep A--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-2-propenoicacid, ethyl ester

Bis(triphenylphosphine) palladium (II) chloride (11.7 g, 16.6 mmol, 4mol %) and ethyl acrylate (226 ml, 2.08 mol) were dissolved in DMF (600ml) and Et₃ N (600 ml) and heated to reflux under an inert atmosphereuntil a homogenous solution resulted. The bromopyrazole (150 g, 0.42mol, see Step C, Example 1) was then added and the resulting solutionheated to reflux overnight, an additional 2 g of the catalyst was alsoadded. The reaction was then cooled and partitioned between ether andwater. The organic layer was separated and washed with water and brine,dried over MgSO₄, concentrated in-vacuo to yield 191 g of a yellow solidwhich was recrystallized from 5:1 hexane/ethyl acetate to yield 105 g ofwhite colorless crystals (67%), mp 114°-116° C.

'H NMR (CDCl₃) δ 8.28 (dd, 1H), 7.77 (m, 1H), 7.56 (m, 2H), 7.0-7.3 (m,4H), 6.0 (d, 1H), 4.2 (q, 2H), 3.34 (m, 1H), 1.62 (d, 6H), 1.28 (tr, 3H)ppm.

Step B--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-2-propen-1-ol

To a solution of the unsaturated ester (50 g, 0.132 mol, Step A) in CH₂Cl₂ (350 ml) at -78° C. under an inert atmosphere was added di-isobutylaluminum hydride (290 ml, 0.29 mol, 1 M soln. in CH₂ Cl₂) dropwise.After stirring for one hour at -78° C., the reaction was quenched byaddition of a saturated aqueous solution of sodium sulphate (41 g) andremoval of the cooling bath. The reaction mixture was allowed to warm toroom temperature and then filtered through celite and sand. The filtratewas dried over MgSO₄, filtered and concentrated in-vacuo to yield awhite solid which was recrystallized from EtOAc-Hexane (1:1) to give34.1 g of pure product (77%), mp 106°-109° C.

'H NMR (CDCl₃): δ 8.28 (dd, 1H), 7.74 (m, 1H), 7.0-7.3 (m, 6H), 6.4 (d,1H), 5.9 (dtr, 1H), 4.2 (br.d, 2H), 3.2 (m, 1H), 2.4 (d, 6H) ppm.

Step C--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-2-propenal

Manganese IV dioxide (72.2 g, 0.83 mol) was suspended in toluene andrefluxed for four hours with azeotropic removal of water. Theunsaturated alcohol (28 g, 0.083 mol, Step B) was added and heating toreflux continued for 24 hours. The suspension was then cooled to roomtemperature and filtered through a bed of silica. The filtrate wasconcentrated in-vacuo to give 27.0 g of pure product (98%), mp 105°-107°C.

'H NMR (CDCl₃) δ 9.45 (d, 1H), 8.25 (d, 1H), 2.75 (m, 1H), 7.58 (d, 1H),7.0-7.3 (m, 6H), 6.36 (dd, 1H), 3.26 (m, 1H), 1.42 (d, 6H) ppm.

Step D--Preparation oftrans-7-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-5-hydroxy-3-oxo-6-heptenoicacid, ethyl ester

To a hexane washed suspension of NaH (1.8 g, 60% oil dispersion, 45.0mmol) in THF (50 ml) at 0° C. under an inert atmosphere, was added asolution of ethyl acetoacetate (5.23 ml, 41 mmol) in THF (40 ml). Theresulting clear solution was stirred at 0° C. for 20 minutes beforen-BuLi (17.1 ml, 41 mmol, 2.4 M soln. in hexane) was added dropwise. Theresulting orange solution was stirred at 020 C. for an additional 15minutes before it was cooled to -78° C. and a solution of theunsaturated aldehyde (12.5 g, 37.3 mmol, Step C) in THF (50 ml) wasadded dropwise over 20 minutes. The resulting solution was stirred at-78° C. for one hour and then quenched by the addition of glacial aceticacid (20 ml) and removal of the cooling bath. The reaction mixture wasthen partitioned between EtOAc and water. The organic extracts werewashed with water, dried over MgSO₄, filtered and concentrated in-vacuoto yield a product which was flash chromatographed on silica gel.Elution with 25% EtOAc-toluene gave 9.0 g of product (52%) and 5.1 g ofstarting unsaturated aldehyde (Step C) which was resubmitted to thereaction conditions to yield an additional 5.2 g of product.

'H NMR (CDCl₃) δ 8.2 (d, 1H), 6.8-7.5 (m, 7H), 6.2 (d, 1H), 5.5 (dd,1H), 4.4 (m, 1H), 4.0 (q, 2H), 3.3 (s, 2H), 3.1 (m, 1H), 2.5 (d, 2H),1.3 (d, 6H), 1.1 (tr, 3H) ppm.

Step E--Preparation of (R*, S*,trans)-7-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptenoicacid, ethyl ester

Triethylborane (33.8 ml 1 M soln. in THF, 33.8 mmol) was added via asyringe to a soution of the β-keto ester (14.3 g, 30.7 mmol, Step D) andpivalic acid (0.31 g, 3.07 mmol) in THF (100 ml) under a dry airatmosphere with stirring. This was stirred at room temperature for fiveminutes before cooling to -78° C. Methanol (12 ml) was added followed bysodium borohydride (1.28 g, 33.8 mmol). The resulting solution wasstirred at -78° C. for six hours. The reaction was quenched by slowaddition to an ice cold solution of 30% hydrogen peroxide (60 ml). Thiswas allowed to warm to room temperature overnight. The reaction mixturewas then partitioned between CHCl₃ and water. The organic extracts werewashed exhaustively with water and dried over MgSO₄, filtered andconcentrated in-vacuo to yield 16.8 g of crude product which was used inthe next step without further purification.

Step F--Preparation of[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl]ethenyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

The dihydroxy ester (16.8 g, 35.9 mmol, Step E) was dissolved in THF(150 ml) and MeOH (100 ml) and 1 N NaOH (36 ml, 35.9 mmol) was added.The resulting solution was stirred at room temperature for one hour, andthen concentrated in-vacuo. The residue was re-dissolved in water andwashed with diethyl ether. The aqueous solution was then acidified with1 N HCL and then extracted with ethyl acetate. The organic extract waswashed extensively with water, dried over MgSO₄, filtered andconcentrated in-vacuo to yield crude dihydroxy acid. This was thenre-dissolved in toluene (200 ml) and heated to reflux with azeotropicremoval of water for three hours. This was then cooled to roomtemperature and concentrated in-vacuo. The residue was flashchromatographed, elution with 25% EtOAc-toluene gave 10 g of productwhich was recrystallized from toluene to give 6.33 g of pure whiteproduct, mp 131°-133° C.

'H NMR (CDCl₃) δ 8.25 (d, 1H), 7.74 (m, 1H), 7.4 (m, 1H), 7.0-7.2 (m,5H), 6.4 (d, 1H), 5.6 (dd, 1H), 5.15 (m, 1H), 4.3 (m, 1H), 3.22 (m, 1H),2.7 (m, 2H), 1.7-2.0 (m, 3H), 1.38 (d, 6H) ppm.

EXAMPLE 3 Preparation of[4α,6β(E)]-6-[2-[5-(4-Fluorophenyl-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-oneStep A--Preparation of2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1H)-pyrazol-1-yl]pyrazine

The hydrazino pyrazine (20.20 g, 183 mmol, prepared as in J. Org. Chem.,27, 3243 (1962)) was added in portions to the 1,3-diketone (34.7 g, 167mmol, prepared in Example 1, Step A) in glacial acetic acid (400 ml).The reaction was refluxed for two hours, concentrated, and partitionedbetween EtOAc and K₂ CO₃ (aq). The organics were dried (MgSO₄) andevaporated to give a brown solid. Recrystallization from hexanesafforded 29.27 g (62%) of a cream colored solid.

'H NMR Spectrum (CDCl₃) δ 8.84 (s, 1H), 8.34 (d, 1H), 8.17 (m, 1H),7.30-6.83 (m, 4H), 6.29 (s, 1H), 3.20-2.89 (m, 1H), 1.35 (d, 6H) ppm.

Step B--Preparation of2-[4-bromo-5-(4-Fluorophenyl)-3-(1-methylethyl-1H-pyrazol-1-yl]pyrazine

N-Bromosuccinimide (18.45 g, 104 mmol) was added in one portion to asolution of the above pyrazole (29.2 g, 104 mmol) in DMF (500 ml) at 0°C. under an inert atmosphere. This was allowed to warm to roomtemperature overnight. The reaction was poured into 500 ml ice water.The precipitate was collected and dried on a vacuum filter to give 33.00g (88%) of product as a white solid.

'H NMR (CDCl₃): δ 8.85 (s, 1H), 8.32 (d, 1H), 8.06 (m, 1H), 7.32-6.57(m, 4H), 3.27-2.95 (m, 1H), 1.38 (d, 6H) ppm.

Step C--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]-2-propenoicacid, ethyl ester

Bis(triphenylphosphine) palladium (II) chloride (2.55 g, 3.6 mmol) andethyl acrylate (49.2 ml, 454 mmol) were dissolved in DMF (200 ml) andEt₃ N (200 ml) at reflux under an inert atmosphere. The bromopyrazole(32.82 g, 91 mmol), Step B) was then added and the reaction was refluxedovernight. An additional 0.005 eq of catalyst and 10 ml of ethylacrylate were added to push the reaction to completion. The reaction wascooled and partitioned between H₂ O and EtOAc. The organic layer wasdried (MgSO₄) and evaporated to give a brown oil. Elution from a 6-inchsilica column gave 20.3 g (59%) of a tan solid. Recrystallization fromhexanes produced a brilliant white solid.

'H NMR (CDCl₃): δ 8.91 (s, 1H), 8.32 (d, 1H), 8.05 (m, 1H), 7.42 (d,1H0, 7.26-6.90 (m, 4H), 5.92 (d, 1H), 4.13-3.97 (q, 2H), 3.40-3.07 (m,1H), 1.42 (d, 6H), 1.25 (tr, 3H) ppm.

Step D--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]2-propen-1-ol

Di-isobutyl aluminum hydride (29 ml, 29 mmol) was added dropwise to asolution of the unsaturated ester (5.0 g, 13.1 mmol, Step C) in CH₂ Cl₂(150 ml) at -78° C. under an inert atmosphere. After one hour, reactionwas incomplete and so an additional 1.1 eq of DIBAL was added. After anadditional hour at -78° C, the reaction was quenched by adding 25 mlsaturated aqueous Na₂ SO₄, and removing the cooling bath. The reactionwas filtered through celite and the filtrate was dried (MgSO₄) andevaporated to give an orange oil. Elution from a 3-inch silica column(30% EtOAc/hexanes) gave 2.33 g (52%) of the pyrazinyl-pyrazole productas a yellow solid.

'H NMR (CDCl₃): δ 8.82 (s, 1H), 8.23 (d, 1H), 8.06-7.97 (m, 1H),7.28-6.85 (m, 4H), 6.29 (d, H), 5.79 (dt, 1H), 4.07 (bd, 2H), 3.34-3.03(m, 1H), 1.98 (bs, 1H), 1.40 (d, 6H) ppm.

Also obtained 0.90 g (26%) of 1H-pyrazole product as a white solid, mp119°-123° C.

'H NMR (CDCl₃): δ 7.57 (q, 2H), 7.08 (t, 2H), 6.47 (d, 1H), 5.90 (dt,1H), 4.22 (d, 2H), 3.39 (bs, 2H), 3.33-3.19 (m, 1H), 1.36 (d, 6H) ppm.

Step E--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]-2-propenal

Manganese IV dioxide (13.3 g, 153 mmol) was suspended in toluene (300ml) and refluxed overnight with the azeotropic removal of H₂ O. Theunsaturated alcohol (5.17 g, 15.3 mmol, Step D) was added and reflux wascontinued for four hours. The reaction was cooled and filtered through abed of silica. Filtrate was evaporated to give 4.73 g (92%) of productas a yellow solid.

'H NMR (CDCl₃): δ 9.32 (d, 1H), 8.90 (s, 1H), 8.29 (d, 1H), 8.03 (m,1H), 7.27-6.90 (m, 5H), 6.18 (dd, 1H), 3.35-3.04 (m, 1H), 1.41 (d, 6H)ppm.

Step F--Preparation oftrans-7-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]-5-hydroxy-3-oxo-6-heptenoicacid, ethyl ester

To a hexane washed suspension of NaH (0.90 g, 22.5 mmol) in THF (30 ml)at 0° C. under an inert atmosphere, was added a solution of ethylacetoacetate (2.69 ml, 21.1 mmol) in THF (30 ml). The resulting clearsolution was stirred at 0° C. for 15 minutes before n-BuLi (9.6 ml, 21.1mmol) was added dropwise. The orange solution was stirred at 0° C. for15 minutes before it was cooled to -78° C. and a solution of theunsaturated aldehyde (4.73 g, 14.1 mmol, Step E) in THF (80 ml) wasadded dropwise. This was stirred at -78° C. for two hours and then itwas quenched by adding˜5 ml HOAc and removing the cooling bath. Thereaction was partitioned between Et₂ O and 5% K₂ CO₃ (aq). The organicswere dried (MgSO₄) and evaporated to give a yellow oil. Elution from a4-inch silica column gave 3.17 g (48%) of product as a yellow foam.

'H NMR (CDCl₃) δ 8.87 (s, 1H), 8.27 (d, 1H), 8.04 (m, 1H), 7.27-6.87 (m,4H), 6.31 (d, 1H), 5.62 (dd, 1H), 4.67-4.42 (m, 1H), 4.25-4.01 (q, 2H),3.40 (s, 2H), 3.31-3.00 (m, 1H), 2.69 (d, 2H), 1.40 (d, 6H), 1.25 (tr,3H) ppm.

Step G--Preparation of (R*, S*,trans)-7-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptenoic acid, ethyl ester

Triethyl borane (7.5 ml, 7.5 mmol) was added via syringe to a solutionof the β-keto ester (3.17 g, 6.8 mmol, Step F) and pivalic acid (0.069g, 0.68 mmol) in THF (50 ml) under a dry air atmosphere. The resultingorange solution was cooled to -78° C. and MeOH (10 ml) was added,followed by NaBH₄ (0.28 g, 7.5 mmol). The resulting effervescentsolution was stirred at -78° C. for five hours. The reaction wasquenched by slowly pouring into ice cold H₂ O₂ (5 ml, 30%) and allowingto stir overnight. The reaction was partitioned between H₂ O and CHCl₃.The organics were washed extensively with H₂ O, dried (MgSO₄) andevaporated to give 2.65 g (84%) of a yellow foam which was used in thenext step without purification.

Step H--Preparation of(R*,S*,trans)-7-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptenoicacid

The dihydroxy ester (2.65 g, 5.7 mmol, Step G) was dissolved in THF (50ml) and 1 N NaOH (5.7 ml, 1.0 eq) was added along with MeOH (5 ml) tomix the two phases. The resulting yellow solution was stirred for threehours at room temperature and then it was concentrated to give thesodium salt of the acid. This was partitioned between H₂ O and Et₂ O.The aqueous layer was then acidified with 1 N HCl and extracted withEtOAc. The organic layer was dried (MgSO₄) and evaporated to give 1.86 g(75%) of a tan foam.

Step I--Preparation of [4α,6β(E)]-6-[2-[5-(4-Fluorophenyl-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]ethenyl]-tetrahydro-4-hydroxy-2-H-pyran-2-one

The dihydroxy acid (1.86 g, 4.2 mmol) was dissolved in toluene (600 ml)and heated to reflux with the azeotropic removal of H₂ O, for ninehours. The reaction was then stirred at 90° C. overnight. The reactionwas cooled and concentrated to give an orange oil. Elution from a 4-inchsilica column gave 0.45 g (47%) of product as an off-white solid.

'H NMR (CDCl₃): 8.92 (s, 1H), 8.37 (d, 1H), 8.13 (m, 1H), 7.27-7.05 (m,4H), 6.40 (d, 1H), 5.70 (dd, 1H), 5.18 (m, 1H), 4.38-4.27 (m, 1H),3.28-3.17 (m, 1H), 2.78-2.49 (m, 5H), 1.41 (d, 6H) ppm.

EXAMPLE 4 Preparation of [4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1)-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-oneStep A--Preparation of2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine

To a solution of 1-(4-fluorophenyl)-4-methyl-1,3-pentanedione(preparation disclosed in Example 1, Step A) (155 g, 0.74 mol) in 1 lglacial acetic acid was added, under a N₂ atmosphere at roomtemperature, 90 g (0.82 mol) of 2-hydrazinopyrimidine (preparedaccording to J. Chesterfield et al., J. Chem. Soc., 3478, 1955). Thiswas heated to 60° C. for one hour, cooled to room temperature and pouredinto 4 l saturated NaHCO₃ aqueous solution. The resulting mixture wasextracted with EtOAc and the organic layer was separated and washed withwater and brine. This solution was dried over MgSO₄, filtered andconcentrated in vacuo. The crude reaction mixture was flashchromatographed on a silica gel column, eluting with 10% EtOAc-tolueneyielding 16.4 g of2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine and94 g of 5(3)-4-fluorophenyl)-3(5)-(1-methylethyl)-1H-pyrazole, mp102°-103° C.

90 MHz (CDCl₃) NMR data for both compounds was as follows:

Compound (1): δ8.5 (d, 2H), 6.8-7.3 (m, 5H), 6.2 (s, 1H), 3.1 (m, 1H),and 1.3 (d, 6H) ppm

Compound (2): δ 7.5 (m, 2H), 6.7-7.1 (m, 2H), 6.1 (s, 1H), 2.8 (m, 1H),and 1.1 (d, 6H) ppm.

Step B--Preparation of2-[4-bromo-5-(4-Fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine

N-Bromosuccinimide (9.97 g, 0.056 mol) was added to a solution of2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H- pyrazol-1-yl]pyrimidine(15.8 g, 0.056 mol) in DMF at 0° C. The resulting mixture was allowed towarm to room temperature over 24 hours. This was then poured into 500 mlwater. The white solid which precipitated was collected by filtrationand dried to yield 16.7 g of2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine(3), mp 130°-133° C.

90 MHz 'H NMR (CDCl ): δ 8.4 (d, 2H), 6.9-7.3 (m, 5H), 3.2 (m, 1H), 1.4(d, 6H) ppm.

Step C--Preparation oftrans-3-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazole-2-propenoicacid, ethyl ester

Ethyl acrylate (16.2 ml, 0.15 mol) and bis-(triphenylphosphine)palladium (II) chloride (0.84 g, 0.0012 mol) in DMF (75 ml) and Et₃ N(75 ml) was heated together at reflux under N₂ with stirring until ahomogeneous solution resulted.2-[4-Bromo-5-(4-fluorophenyl))-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine(3) (10.8 g, 0.03 mol) was added and the resulting solution was heatedat reflux for 24 hours, during which, an additional 1 mol % of catalystwas added. The mixture was then cooled to room temperature and dilutedwith ether and water. The organic layer was separated and washed withwater and brine, dried over MgSO₄, filtered and concentrated in vacuo.The resulting solid (10.4 g) was recrystallized from hexane/ethylacetate, mp 155°-162° C.

'H NMR (CDCl₃): δ 8.5 ppm (d, 2H), δ 7.3 (d, 1H, J=24 Hz), 6.9-7.2 (m,5H), 5.8 (d, 1H, J=24 Hz), 41 (q, 2H), 3.3 (m, 1H), 1.4 (d, 6H), 1.2(tr, 3H) ppm.

Step D--Preparation oftrans-5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazole-2-propenal

To a solution of trans-5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazole-2-propenoic acid, ethyl ester(10 g, 0.026 mol) in 100 ml of dry CH₂ Cl₂ at -78° C. was added dropwise2.5 equivalents of a solution of di-isobutyl aluminum hydride (1 M inCH₂ Cl₂) under a N₂ atmosphere. After addition, the resulting solutionwas stirred at -78° C. for two hours, the cooling bath was removed andthe reaction quenched by the addition of 10 g (2.5 eq) of a saturatedaqueous solution of sodium sulphate. The resulting mixture was filteredthrough diatomaceous earth and sand. The solids were washed with hotEtOAc and the combined filtrates were dried over MgSO₄, filtered andconcentrated in vacuo. Flash chromatography of the crude reactionmixture eluting with 25% EtOAc-toluene gave 2.0 g of a productidentified as starting material. Also eluted was 1.6 g of a producttentatively assigned the dihydropyrimidine structure.

'H NMR (CDCl₃) evidence was as follows: δ6.8 (m, 5H), 5.5-6.1 (m, 4H),4.0 (d, 2H), 3.7 (br.s, 1H), 3.1 (m, 1H), 1.2 (d, 6H) ppm.

This crude product (1.6 g) was dissolved in toluene and added to arefluxing toluene suspension of MnO₂ (23.4 g, 0.27 mol). This was heatedat reflux overnight with azeotropic removal of water using a Deans Starkapparatus. This was then cooled to room temperature and the suspensionwas then filtered through celite and silica gel. The filtrate wasconcentrated in-vacuo and the resulting solid recrystallized fromEtOAc-hexane, mp 115°-125° C.

'H NMR (CDCl₃) δ9.4 (d, 1H), 8.4 (d, 2H), 7.0-7.3 (m, 6H), 6.1-6.4 (d ofd, 1H), 3.3 (m, 1H), 1.4 (d, 6H) ppm.

Step E--Preparation oftrans-7-(4-Fluorophenyl-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]-5-hydroxy-3-oxo-6-heptenoicacid, ethyl ester

To a stirred suspension of 0.3 g (0.0074 mol, 60% NaH) of hexane washedNaH in 25 ml THF cooled to 0° C. under N₂ was added a solution of ethylacetoacetate (0.88 ml, 0.0069 mol) in THF (10 ml). When gas evolutionwas complete, 2.8 ml (0.0069 mol) of a 2.5 M hexane solution of n-butyllithium was added dropwise. The resulting solution was stirred anadditional 30 minutes at 0° C. and then cooled to -78° C. A solution of1.55 g (0.046 mol) of the compound of Step D in 15 ml THF was addeddropwise. The resulting solution was stirred at -78° C. for a furthertwo hours when the reaction was quenched by addition of 10 ml glacialacetic acid. The mixture was partitioned between water and EtOAc. Theorganic layer was separated, washed with water and brine and dried overMgSO₄, filtered and evaporated to yield a yellow oil which was flashchromatographed on silica gel eluting with 40% EtOAc-toluene giving 0.5g of starting material and 0.6 g of the desired compound which was usedin the next step without any further purification.

'H NMR (CDCl₃) δ 8.5 ppm (d, 2H), 6.9-7.3 (m, 5H), 6.3 (d, 1H), 5.5 (dof d, 1H), 4.2 (m, 1H), 4.1 (q, 2H), 3.2 (s, 2H), 3.1 (m, 1H), 2.6 (d,2H), 1.4 (d, 6H), 1.2 (tr, 3H) ppm.

Step F--Preparation of [4α,6β(E)]-6-[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]ethenyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

Triethylborane (1.42 ml, 1 M solution, 0.00142 mol) was added in asingle portion to a solution of the compound of Step E (0.6 g, 0.00129mol) and 13.2 mg of pivalic acid (0.00013 mol) in THF (40 ml) under adry air atmosphere. This solution was stirred for five minutes before 10ml of air was bubbled through the solution. The mixture was then cooledto -78° C. and 5 ml MeOH and 53.6 mg of NaBH₄ were added. The mixturewas stirred at -78° C. for six hours and then poured into 15 ml of 30%aqueous H₂ O₂. This was stirred at room temperature overnight and thendiluted with water and extracted with CHCl₃. The organic layer wasseparated, washed with water and brine, dried over MgSO₄, filtered andevaporated to yield 0.6 g of the dihydroxy ester which was used withoutfurther purification.

The above compound (0.6 g) was dissolved in methanol (20 ml) and 1.28 ml1 N NaOH was added. This solution was stirred at room temperature forthree hours. The solution was then concentrated and the resultingresidue re-dissolved in water. This aqueous layer was acidified with 1 NHCl and then extracted with EtOAc. The organic layer was washed withwater and brine and dried over MgSO₄, filtered and evaporated to yield0.4 g crude product. This was re-dissolved in toluene (75 ml) and theresulting mixture was heated under reflux for four hours with azeotropicremoval of water. The reaction mixture was then concentrated and theresidue flash chromatographed on silica gel eluting with 50%EtOAc-toluene, to yield 0.17 g of the title compound, mp 164°-166° C.

'H NMR (CDCl₃) δ 8.6 (d, 2H), 7.0-7.2 (m, 5H), 6.3-6.4 (d, 1H), 5.6-5.7(d of d, 1H), 5.2 (m, 1H), 4.3 (m, 1H), 3.2 (m, 1H), 2.5-2.7 (m, 2H),1.7-1.9 (m, 2H), 1.4 (d, 6H) ppm.

EXAMPLE 5 Preparation of[4α,6β(E)]-6-[2-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-oneStep A--Preparation of2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]benzothiazole

To a solution of the 1,3-diketone (103 g, 495 mmol) (preparationdescribed in Example 1, Step A) in glacial acetic acid (800 ml) wasadded 2-hydrazinobenzothiazole (85.8 g, 520 mmol). The resultingsolution was refluxed for 2.5 hours and then cooled to room temperatureovernight. The resulting precipitate was collected, washed with waterand dried overnight to give 154 g (92%) of a cream colored solid.

'H NMR Spectrum (CDCl₃): δ 7.80 (dd, 1H), 7.68 (dd, 1H), 7.58-7.50 (m,2H), 7.42-7.27 (m, 2H), 7.16-7.07 (m, 2H), 6.35 (s, 1H), 3.17-3.03 (m,1H), 1.35 (d, 6H) ppm.

Step B--Preparation of2-[4-Bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]benzothiazole

N-Bromosuccinimide (86.5 g, 486 mmol) was added in portions to thepyrazole (164 g, 486 mmol, Step A) in DMF (1l) at 0° C. under anatmosphere of N₂. This mixture was stirred and allowed to warm to roomtemperature overnight. The reaction mixture was poured into H₂ O (1 l)and the resulting precipitate was collected and washed with water. Theproduct was dried overnight to give 184.1 g (91%), mp 146°-147° C.(hexanes).

'H NMR Spectrum (CDCl₃) δ 7.79 (dd, 1H), 7.64 (d, 1H), 7.55-7.48 (m,2H), 7.40-7.28 (m, 2H), 7.22-7.15 (m, 2H), 3.23-3.14 (m, 1H), 1.44 (d,6H) ppm.

Step C--Preparation oftrans-3-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl-3-(1-methylethyl)-1H-pyrazol-4-yl]-2-propenoicacid, ethyl ester

Ethyl acrylate (39 ml, 360 mmol) and the palladium catalyst (2.02 g, 2.9mmol) (previously described) were mixed in DMF (100 ml) and Et₃ N (100ml) and heated to reflux to give a homogeneous solution. Thebromopyrazole (30 g, 72 mmol, Step B) was added and the reaction wasrefluxed for 24 hours under an inert atmosphere. The reaction wascooled, and partitioned between H₂ O and Et₂ O. The combined organicextracts were dried (MgSO₄) and evaporated to give a brown oily solid.Recrystallization from hexanes gave 23.60 g (75%) of product as a creamcolored solid.

'H NMR Spectrum (CDCl₃) δ 7.75 (dd, 1H), 7.60 (dd, 1H), 7.53-7.16 (m,7H), 6.00 (d, 1H), 4.19 (q, 2H), 3.33-3.23 (m, 1H), 1.44 (d, 6H),1.31-1.25 (tr, 3H) ppm.

Step D--Preparation oftrans-3-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl-3-(1-methylethyl)-1H-pyrazol-4-yl]-2-propen-1-ol

To a suspension of the unsaturated ester (23.60 g, 54 mmol, Step C) inCH₂ Cl₂ (400 ml) at -78° C. under an inert atmosphere, was added,dropwise, a solution of di-isobutyl aluminum hydride in methylenechloride (119 ml, 119 mmol). The reaction was stirred for 1.5 hours andTLC. indicated incomplete reaction. An additional aliquot of di-isobutylaluminum hydride (60 ml, 60 mmol) was added dropwise and the reactionwas stirred for an additional 2.5 hours at -78° C. The reaction wasquenched by adding 100 ml saturated Na₂ SO₄ solution and removing thecooling bath. The reaction was stirred at room temperature overnight andfiltered through diatomaceous earth. The filtrate was dried (MgSO₄) andevaporated to give 13.82 g (65%) of a tan solid which was used in thenext step without further purification.

'H NMR Spectrum (CDCl₃): δ 7.72 (d, 1H), δ7.60 (d, 1H), 7.56-7.12 (m,6H), 6.30 (d, 1H), 5.95-5.85 (dtr, 1H), 4.17 (d, 2H), 3.28-3.17 (m, 1H),1.98 (br.s., 1H), 1.42 (d, 6H) ppm.

Step E--Preparation oftrans-3-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-2-propenal

Manganese dioxide (30.0 g, 350 mmol) was suspended in toluene (600 ml)and refluxed overnight under an inert atmosphere, with azeotropicremoval of H₂ O. The crude unsaturated alcohol (13.82 g, 35 mmol, StepD) was added and the reaction was heated to reflux for eight hours withthe azeotropic removal of H₂ O. The reaction was cooled to roomtemperature overnight, concentrated to dryness and the residue waseluted from a 4-inch silica column (CH₂ Cl₂ /EtOAc) to give 7.5 g (55%)product as a white solid.

'H NMR Spectrum (CDCl₃): δ 9.37 (d, 1H), 7.75-6.97 (m, 9H), 6.23 (dd,1H), 3.32-3.02 (m, 1H), 1.44 (d, 1H) ppm.

Step F--Preparation oftrans-7-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-5-hydroxy-3-oxo-6-heptenoicacid, ethyl ester

To a hexane washed suspension of NaH (1.23 g, 30.7 mmol) in THF (20 ml)at 0° C. under an inert atmosphere, was added a solution of ethylacetoacetate (3.66 ml, 28.7 mmol) in THF (20 ml). The resulting clearsolution was stirred at 0° C. for 15 minutes before n-BuLi (13.1 ml,28.7 mmol) was added dropwise. This orange solution was stirred at 0° C.for 15 minutes before it was cooled to -78° C. and a solution of theunsaturated aldehyde (7.50 g, 19.2 mmol, Step E) in THF (100 ml) wasadded dropwise. The reaction was stirred at -78° C. for one hour andthen it was quenched by adding 4 ml glacial acetic acid and removing thecooling bath. The reaction mixture was partitioned between Et₂ O andsaturated aqueous K₂ CO₃ solution. The organic extracts were dried(MgSO₄) and evaporated to give an orange solid. Recrystallization fromhexanes gave 8.71 g (87%) of product as a pale yellow orange solid.

'H NMR Spectrum (CDCl₃): δ 7.70-6.90 (m, 8H), 6.32 (d, 1H), 5.60 (dd,1H), 4.90-4.48 (m, 1H), 4.27-4.03 (q, 2H), 3.39 (s, 2H), 3.30-2.95 (m,1H), 2.80 (br.s., 1H), 2.65 (d, 2H), 1.40 (d, 6H), 1.32-1.14 (tr, 3H)ppm.

Step G--Preparation of(R*,S*,trans)-7-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-3,5-dihydroxy-6-heptenoicacid, ethyl ester

Triethyl borane (17.3 ml, 17.3 mmol) was added via syringe to a solutionof the β-keto ester (8.18 g, 15.7 mmol, Step F) and pivalic acid (0.16g, 1.6 mmol) in THF (150 ml) under a dry air atmosphere. The resultingorange solution was stirred for 15 minutes at room temperature. Thereaction was then cooled to -78° C. and MeOH (20 ml) was added, followedby addition of NaBH₄ (0.65 g, 17.3 mmol). The resulting solution wasstirred at -78° C. for seven hours before it was quenched by carefullypouring into ice-cold aqueous H₂ O₂ (7 ml, 30%) and stirring overnight.The reaction mixture was partitioned between H₂ O and CHCl₃. The organiclayer was dried (MgSO₄) and evaporated to give 7.40 g (90%) of a yellowfoam which was used in the next step without further purification.

The above dihydroxy ester (7.28 g, 13.9 mmol) was dissolved in 150 mlTHF and 10 ml MeOH, and 1 N NaOH (14.6 ml) was added. This was stirredfor one hour and then evaporated to dryness to give the sodium salt ofthe acid (mp 226°-231° C). This was dissolved in water and washed withdiethyl ether. The aqueous layer was acidified with 1 N HCl andextracted with EtOAc. The organic layer was dried (MgSO₄) and evaporatedto give 5.50 g (80%) of a yellow foam.

Step H--Preparation of[4α,6β(E)]-6-[2-[1-(2-Benzothiazolyl)-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one

The dihydroxy acid (5.50 g, 11.1 mmol, Step G) was dissolved in toluene(500 ml) and the solution was heated to reflux with the azeotropicremoval of H₂ O for five hours. The reaction was cooled and concentratedto give a yellow solid. Elution from a 4-inch silica column (EtOAc) gave4.0 g (75%) of product as an off-white solid, mp 168°-170° C.

'H NMR Spectrum (CDCl₃): δ 7.74 (dd, 1H), 7.59 (dd, 1H), 7.44-7.12 (m,6H), 6.38 (d, 1H), 5.70 (dd, 1H), 5.21-5.13 (m, 1H), 4.40-4.34 (m, 1H),3.26-3.15 (m, 1H), 2.78-2.58 (m, 2H), 2.00-1.78 (m, 2H), 1.73 (br.s.,1H), 1.41 (d, 6H) ppm.

PREPARATION OF STARTING MATERIALS Preparation of5-hydroxy-3-oxo-6-heptenoic acid, ethyl ester

Propenal (0.1 mol, as a 2 M solution in tetrahydrofuran) was addeddropwise over a period of thirty minutes to a stirred solution of 0.11mol of the lithio-sodio salt of ethyl acetoacetate in 200 ml oftetrahydrofuran which had been cooled to 0° C. When addition wascomplete, the solution was stirred for thirty minutes after which thereaction was quenched by the addition of saturated ammonium chloridesolution, followed by 2 M hydrochloric acid solution.

The reaction mixture was extracted with diethyl ether and the etherextract was washed successively with water, saturated sodium bicarbonatesolution, and then brine. The ether solution was then dried overanhydrous magnesium sulfate, filtered, and evaporated to yield 14 g of5-hydroxy-3-oxo-6-heptenoic acid, ethyl ester, contaminated with aslight amount of ethyl acetoacetate starting material.

Preparation of β,δ-dihydroxy-6-heptenoic acid, ethyl ester

Employing a syringe, 10 ml of air were bubbled through a solution of 10mmol of 5-hydroxy-3-oxo-6-heptenoic acid, ethyl ester and 11 mmol oftributylborane dissolved in 10 ml of anhydrous tetrahydrofuran which wasunder a nitrogen atmosphere. The resulting mixture was stirredovernight, then cooled to -78° C. after which 12 mmol of sodiumborohydride were added. The suspension was allowed to warm slowly to 0°C., at which point the reaction was quenched by the addition of 30 mmolof glacial acetic acid. Methanol (30 ml) was added, followed by 3.3 mlof 30% aqueous hydrogen peroxide solution. This mixture was stirred at0° C. for sixty minutes, and then partitioned between diethyl ether andwater.

The organic layer was separated, washed with brine solution, and thendried over anhydrous magnesium sulfate. The ether solution wasevaporated to yield crude β,δ-dihydroxy-6-heptenoic acid, ethyl esterwhich was used in the subsequent step without further purification.

Preparation of 6-ethenyl-2,2-dimethyl-1,3-dioxane-4-acetic acid, ethylester

The crude β,δ-dihydroxy-6-heptenoic acid, ethyl ester from the previousstep was dissolved in a mixture of 30 ml of dichloromethane and 10 ml of2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and themixture was stirred overnight. Concentration of the reaction mixture andflash chromatography of the residue yielded 1.1 g of6-ethenyl-2,2-dimethyl-1,3-dioxane-4-acetic acid, ethyl ester.

The infrared spectrum of a liquid film of the product showed principalabsorption peaks at 2994, 1743, 1439, 1382, 1203, and 1170 cm⁻¹.

The 90 MHz proton magnetic resonance spectrum of a deuterochloroformsolution of the product showed peaks at 1.2-1.5 (m, 10H), 1.60 (m, 1H),2.48 (m, 2H), 3.75 (m, 1H), 4.05 (1, 2H, J=7Hz), 4.35 (m, 1H), 5.0-6.0(m, 3H) parts per million downfield from tetramethyl silane.

We claim:
 1. A compound of structural formula I ##STR6## wherein R₁ is2-, 4-, or 5-pyrimidinyl; or 2-pyrazinyl; and wherein R₁ is attached toone of the nitrogen atoms of the pyrazole nucleus;R₂ is alkyl of fromone to three carbon atoms or trifluoromethyl; R₅ is a saturatedcarbocyclic ring of from four to seven carbon atoms optionallysubstituted with alkyl of from one to three carbon atoms; 2-norbornyl;2-norbornenyl; bicyclo[2.2.2]octyl; or ##STR7## wherein R₃ is alkyl offrom one to three carbon atoms, chlorine or fluorine, and R₄ ishydrogen, alkyl of from one to three carbon atoms, chlorine, orfluorine; or a ring-opened hydroxy acid or ester derived therefrom,N-oxides thereof or a pharmaceutically acceptable salt thereof.
 2. Acompound as defined by claim 1 having the formula ##STR8## where R₅ is##STR9##
 3. A compound as defined in claim 1 having the name[4α,6β]-6-[2-[5-(4-fluorophenyl)-3-(1-methylethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.4. A compound as defined in claim 3 having the name[4α,6β(E)]-6-[2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.5. A compound as defined in claim 3 having the name[4α,6β(E)]4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
 6. Apharmaceutical composition, useful as a hypocholesterolemic agent,comprising a hypocholesterolemic effective amount of a compound inaccordance with claim 1 in combination with a pharmaceuticallyacceptable carrier.
 7. A method of inhibiting cholesterol biosynthesisin a patient in need of such treatment by administering a pharmaceuticalcomposition as defined by claim 6.